Various medicaments have been used in the form of inhalation formulation for the treatment of respiratory diseases, e.g., asthma and chronic obstructive pulmonary disease (COPD). A particular advantage of inhalation formulation is that only a small amount of a pharmaceutically active ingredient is required to achieve the desired therapeutic effect; however, there are drawbacks to the formulation that only a part of the pharmaceutically active ingredient administered will be delivered to a target site, or there is a great possibility that the pharmaceutically active ingredient will be delivered to sites where no treatment is required, thereby causing adverse side effects. Thus, continuous efforts are being made to maximize the therapeutic effect of the formulation so as to achieve reliable targeted delivery to the site where the therapeutic effect is desired and to prevent the delivery of the pharmaceutically active ingredient to the site where no treatment is required.
For effective administration of inhalation formulation, inhalers, which administer the drug by sucking in the air with the drug and delivering them into the air passage, have been widely used for treatment of respiratory diseases. The most common inhaler systems are metered dose inhalers (MDI), which had been used extensively since its approval in 1956, and once occupied 80% of the inhaler market. However, a rise of environmental concerns, e.g., depletion of ozone layer and global warming, has shifted research interests to focus on dry powder inhalers (DPI) in recent years. In current stage, researchers are concentrating their efforts to remedy the shortcomings of MDI formulations by employing DPI formulations. MDIs typically comprise pharmaceutically active ingredients and a solvent as a propellant in compressed state, which deteriorates its stability; and the spraying speed is fast, and thus it reaches laryngopharyngeal space too fast. DPIs, however, are easy to use; and only comprised of powder solid particles, and therefore are advantageous in terms of stability (see Martin J Telko and Anthony J Hickey, Dry Powder Inhaler Formulation, Respiratory Care, September 2005, Vol 50, No. 9).
Meanwhile, various drugs are being tested for the prevention and treatment of respiratory diseases. For example, a selective beta-2 adrenoceptor agonist (beta-2 agonist) can induce bronchodilation, and can be used to relieve respiratory distress. Beta-2 agonists may be broadly divided into short-acting beta-2 agonists and long-acting beta-2 agonists. Short-acting beta-2 agonists, e.g., salbutamol, fenoterol, levalbuterol, terbutaline, etc., provide immediate relief, but their reaction time is rather short. In contrary, long-acting beta-2 agonists, e.g., formoterol, indacaterol, salmeterol, tulobuterol, etc., provide sustained bronchodilation, but patients are required to take them two or more times per day because the normal reaction time of these drugs is less than 12 hours.
Beta-2 agonists can alleviate bronchoconstriction in patients, but other drugs, e.g., steroids, are used to treat inflammation, which is another cause of asthma. Examples of steroids include inhaled corticosteroid (ICS) such as beclomethasone, budesonide, flunisolide, fluticasone propionate, mometasone furoate, triamcinolone, and the like.
Also, another type of drugs called an inhaled anticholinergic is well-known as a stable and effective bronchodilator which can be used for treatment of COPD. Anticholinergic agents can increase the level of forced expiratory volume in 1 second (FEV1), prevent static or dynamic hyperinflation (overexpanded lung), and reduces exacerbations of COPD. There is a limited number of inhaled anticholinergic bronchodilators that are currently available, e.g., rapid-onset types such as ipratropium bromide, oxitropium bromide, etc., and long-acting types such as tiotropium bromide, etc.
Global Initiative for Asthma (GINA) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) are suggesting an incremental treatment method based on the progression of the disease condition, which includes the use of a combination formulation of drugs having different or complementary action mechanisms. For instance, a long-acting beta-2 agonist is prescribed to patients with asthma or COPD having FEV1 level of less than 80%, and COPD patients with accompanying respiratory distress having FEV1 level of less than 50% or who are experiencing frequent acute exacerbations are prescribed with ICS in addition to beta-2 agonists.
A number of combinations of the aforementioned drugs are known already, and one typical example is an inhalation formulation comprising salmeterol xinafoate and fluticasone propionate (Seretide, GSK). Currently, Seretide is available in MDI (Evohaler) and DPI (Diskus) formulations. Seretide provides an effective bronchodilation induced by the long-acting beta-2 agonist salmeterol, as well as potent anti-inflammatory action caused by the ICS, fluticasone propionate. In case of Seretide Diskus formulation, which is provided in the form of DPI formulation, both beta-2 agonist and inhaled corticosteroid may be inhaled at once, but the formulation does not show sustained bronchodilation action, and thus patients are required to take the formulation two or more times per day. Another drawback of this formulation lies in that the amount of the excipient is too small to give a sensation in the lungs upon administration, and sometimes the dose is not properly delivered or is taken two or more times because it is impossible to observe administered formulation.
Also, a combination therapy comprising a rapid-onset anticholinergics ipratropium bromide and a long-acting beta-2 agonist salmeterol is disclosed in WO01/76601, and an additional combination therapy using anticholinergics, beta-2 agonist as well as steroid is disclosed in U.S. Pat. No. 6,423,298 and WO02/7672.
Nevertheless, said formulations do not relate to a triple combination formulation which can exert fast-acting bronchodilation induced by a beta-2 agonist, anti-inflammatory action by a corticosteroid, and sustained bronchodilation by an anticholinergic at once.
Recently, KR Patent Laid-Open Publication No 10-2009-0121338 and US Patent Application Publication No. 2010/0063016 mentioned about a triple combination formulation of beta-2 agonist, corticosteroid, and anticholinergic. However, they neither consider any specific device, effective dose amount, manufacturing method thereof, packaging type, particle size of the carrier material, etc., nor provide assessment data thereof. Pressure drop values of inhalation formulations, especially in the form of dry powder inhalation formulations, vary when different types of devices are used, and the amount of active ingredient delivered to lungs may vary with packaging forms, e.g., blister packaging vs. capsule packaging. Properties and ratio of excipient (such as lactose, etc.), which is used as a carrier, can also cause a large difference in therapeutic effects. Moreover, even if drugs from the same drug group were used, undesirable results such as deterioration in uniformity and storage stability may occur depending on physicochemical properties of the respective drugs.
Although some drugs and a combination formulation thereof for the prevention or treatment of respiratory diseases are known, there are no specific compositions or preparation method thereof developed for a triple combination formulation which can administer a long-acting beta-2 agonist, an inhaled corticosteroid and an anticholinergic together at once. Thus, there has been a need to develop a composition of a composite formulation, which can stably and accurately administer said three groups of drug in a single dose, to improve patient compliance and enhance patients' convenience to carry the formulation.